Claims for Patent: 10,301,262

Summary for Patent: 10,301,262

Title:	Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compund1) for use in SIPI receptor-associated disorders
Abstract:	The present invention relates to, inter alia, a novel crystalline free-plate habit or morphology, processes for preparing the crystalline free-plate habit, and uses of the crystalline free-plate habit of the L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid (Compound 1) in the treatment of S1Preceptor-associated disorders, for example, diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), cancer, and conditions characterized by an underlying defect in the vascular integrity or that are associated with angiogenesis such as may be pathologic (e.g., as may occur in inflammation, tumor development, and atherosclerosis).
Inventor(s):	Blackburn Anthony C., Castro Ryan O., Hadd Mark Allen, Ma You-An, Montalban Antonio Garrido, Rueter Jaimie Karyn, Selvey Lee Alani, Shakya Sagar Raj, Carlos Marlon
Assignee:	Arena Pharmaceuticals, Inc.
Application Number:	US15738175
Patent Claims:	1. A crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 ,2 ,3 ,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; wherein said crystalline free-plate habit has a BET specific surface area of about 0.1 m/g to about 5.0 m/g.2. The crystalline free-plate habit according to claim 1 , having a BET specific surface area of about 0.6 m/g to about 4.0 m/g.3. A crystalline free-plate habit according to or claim 1 , having a powder X-ray diffraction pattern comprising peaks claim 1 , in terms of 2θ claim 1 , at 8.2°±0.2° claim 1 , 16.4°±0.2° claim 1 , and 20.5°±0.2°.4. The crystalline free-plate habit according to or claim 1 , having a powder X-ray diffraction pattern comprising peaks claim 1 , in terms of 2θ claim 1 , at 8.2°±0.2° claim 1 , 16.4°±0.2° claim 1 , 20.5°±0.2° claim 1 , and 24.6°±0.2°.5. The crystalline free-plate habit according to or claim 1 , having a powder X-ray diffraction pattern comprising peaks claim 1 , in terms of 2θ claim 1 , at 8.2°±0.2° claim 1 , 16.4°±0.2° claim 1 , 20.5°±0.2° claim 1 , 24.6°±0.2° claim 1 , 28.8°±0.2° claim 1 , and 37.3°±0.2°.6. The crystalline free-plate habit according to claim 1 , having a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.0° C. to 208.5° C. at a scan rate of 10° C./minute.7. The crystalline free-plate habit according to claim 1 , having a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5° C. to 208.1° C. at a scan rate of 10° C./minute.8. The crystalline free-plate habit according to claim 1 , having a differential scanning calorimetry trace conducted at a scan rate of 10° C./minute comprising an endotherm substantially as depicted in any one of and .9. The crystalline free-plate habit according to claim 1 , having a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein said crystalline free-plate habit gains about 0.3% weight or less at 90% RH.10. The crystalline free-plate habit according to claim 1 , having:1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, and 24.6°±0.2°;2) a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5° C. to 208.5° C. at a scan rate of 10° C./minute;3) a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein said crystalline free-plate habit gains about 0.3% weight or less at 90% RH; and/or{'sup': 2', '2, '4) a BET specific surface area of about 0.6 m/g to about 4.0 m/g.'}11. The crystalline free-plate habit according to claim 1 , having:1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°, 28.8°±0.2°, and 37.3°±0.2°;2) a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5° C. to 208.1° C. at a scan rate of 10° C./minute;3) a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein said crystalline free-plate habit gains about 0.2% weight or less at 90% RH; and/or{'sup': 2', '2, '4) a BET specific surface area of about 0.6 m/g to about 4.0 m/g.'}12. A composition comprising a crystalline free-plate habit of L-arginine salt of (R)-2-(7(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 1 ,2 claim 1 ,3 claim 1 ,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid according to .13. A pharmaceutical composition comprising a crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 1 ,2 claim 1 ,3 claim 1 ,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid according to and a pharmaceutical excipient.14. The pharmaceutical composition according to claim 13 , wherein said pharmaceutical composition is suitable for oral administration.17. The method according to claim 16 , wherein said hydrolyzing-step solvent comprises acetonitrile.19. The method according to any one of to claim 16 , wherein said hydrolyzing is conducted in the presence of a phosphate buffer at a pH of about 6.9 to about 8.1 claim 16 , wherein said phosphate buffer is a potassium phosphate buffer.20. The method according to claim 16 , wherein said hydrolyzing is conducted at a temperature of about 35° C. to about 45° C.21. The method according to claim 16 , wherein after said hydrolyzing claim 16 , said (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 16 ,2 claim 16 ,3 claim 16 ,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid is not isolated.22. The method according to claim 21 , wherein after said hydrolyzing claim 21 , said (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 21 ,2 claim 21 ,3 claim 21 ,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid is present in an amount of at least 40% as determined by HPLC.23. The method according to claim 16 , wherein forming said first mixture in Step b) comprises the step of adding L-arginine and HO claim 16 , either together or separately in any order claim 16 , to a salt-forming mixture comprising (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 16 ,2 claim 16 ,3 claim 16 ,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and said water-miscible anti-solvent to form said first mixture.24. The method according to claim 23 , wherein said adding L-arginine and HO is conducted under an inert atmosphere comprising nitrogen.25. The method according to claim 16 , wherein said water-miscible anti-solvent comprises a solvent selected from the group consisting of: acetonitrile claim 16 , acetone claim 16 , tetrahydrofuran claim 16 , and C-Calkanol.26. The method according to claim 16 , wherein said water-miscible anti-solvent comprises 2-propanol.27. The method according to claim 23 , wherein prior to adding said L-arginine and HO claim 23 , said salt-forming mixture comprises (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 23 ,2 claim 23 ,3 claim 23 ,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid and 2-propanol in a weight ratio of about 1.0:6.0 to about 1.0:8.0.28. The method according to claim 23 , wherein the molar ratio between (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 23 ,2 claim 23 ,3 claim 23 ,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0:0.93 to about 1.0:1.01.29. The method according to claim 23 , wherein the weight ratio of L-arginine and HO is about 1.0:1.2 to about 1.0:1.5.30. The method according to claim 23 , wherein said salt-forming mixture prior to said adding L-arginine is at a temperature of about 18° C. to about 30° C.31. The method according to claim 23 , wherein said salt-forming mixture comprises (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 23 ,2 claim 23 ,3 claim 23 ,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid claim 23 , 2-propanol claim 23 , and water in a weight ratio of about 1.0:6.0:0.25 to about 1.0:8.0:0.7.32. The method according to claim 23 , wherein said salt-forming mixture during said adding L-arginine is at a temperature of about 18° C. to about 30° C.33. The method according to claim 16 , wherein said second mixture is substantially a homogeneous solution.34. The method according to claim 16 , wherein the weight ratio of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 16 ,2 claim 16 ,3 claim 16 ,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to said first additional amount of 2-propanol is about 1.00:5.95 to about 1.00:6.25.35. The method according to claim 16 , wherein said first additional amount of said water-miscible anti-solvent is added during a first time point and a second time point.36. The method according to claim 35 , wherein about 8% to about 12% of said first additional amount of said water-miscible anti-solvent is added at said first time point.37. The method according to claim 35 , wherein said first additional amount of said water-miscible anti-solvent is added at said first time point to form a cloudy mixture.38. The method according to claim 35 , wherein prior to said second time point claim 35 , a seed crystal of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 35 ,2 claim 35 ,3 claim 35 ,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid is optionally added.39. The method according to claim 35 , wherein said first additional amount of said water-miscible anti-solvent is added at said second time point at a rate to complete the addition in about 1.00 hour or greater.40. The method according to claim 16 , wherein cooling said suspension to said first cooling temperature in Step e) is conducted at a rate of about 9° C./hour to about 11° C./hour.41. The method according to claim 16 , wherein said cycling in Step f) comprises said cycling Step e) two times.42. The method according to claim 41 , wherein said cycling Step e) two times comprises cooling the suspension to a first cycling cooling temperature claim 41 , heating the suspension to a first cycling heating temperature claim 41 , cooling the suspension to a second cycling cooling temperature claim 41 , and heating the suspension to a second cycling heating temperature.43. The method according to claim 42 , wherein said first cycling cooling temperature is about 16° C. to about 26° C. claim 42 , said first heating cycling temperature is about 55° C. to about 65° C. claim 42 , said second cycling cooling temperature is about 26° C. to about 36° C. claim 42 , and said second cycling heating temperature is about 45° C. to about 55° C.44. The method according to claim 16 , wherein said cycling in Step f) comprises said cycling Step e) three times.45. The method according to claim 44 , wherein said cycling Step e) three times comprises: cooling the suspension to a first cycling cooling temperature claim 44 , heating the suspension to a first cycling heating temperature claim 44 , cooling the suspension to a second cycling cooling temperature claim 44 , heating the suspension to a second cycling heating temperature claim 44 , cooling the suspension to a third cycling cooling temperature claim 44 , and heating the suspension to a third cycling heating temperature.46. The method according to claim 45 , wherein said first cycling cooling temperature is about 16° C. to about 26° C. claim 45 , said first heating cycling temperature is about 66° C. to about 76° C. claim 45 , said second cycling cooling temperature is about 16° C. to about 26° C. claim 45 , said second cycling heating temperature is about 55° C. to about 65° C. claim 45 , said third cycling cooling temperature is about 26° C. to about 36° C. claim 45 , and said third cycling heating temperature is about 45° C. to about 55° C.47. The crystalline free-plate habit according to claim 1 , having:1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, and 20.5°±0.2°;2) a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.0° C. to 208.5° C. at a scan rate of 10° C./minute; and/or3) a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein said crystalline free-plate habit gains about 0.3% weight or less at 90% RH.48. A pharmaceutical composition comprising a crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 10 ,2 claim 10 ,3 claim 10 ,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid according to claim 10 , and a pharmaceutical excipient.49. A pharmaceutical composition comprising a crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 11 ,2 claim 11 ,3 claim 11 ,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid according to claim 11 , and a pharmaceutical excipient.50. A pharmaceutical composition comprising a crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 claim 47 ,2 claim 47 ,3 claim 47 ,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid according to claim 47 , and a pharmaceutical excipient.